Can human embryonic stem cells model human nutrition?

Human embryonic stem cell colony

Scientists at Harvard University have proposed a new model for studying nutrition, human embryonic stem cells. Human embryonic stem cells are unique in their ability to turn into all the cell types in the body, including the various tissue types in the human gut.

Drs. Doug Melton and Danny Ben-Zvi propose in an essay in Cell that human embryonic stem cell derived tissues populated by gut microbiota may be an ideal system for studying the physiology of digestion and nutrition. The authors state that the mechanisms of human nutrition are largely unknown and that it is difficult to model how nutrition affects human health on a biological front. By developing systems of stem cell derived tissues, it may be possible to model the gut in the petri dish or even on a chip. Significant engineering advances have been made to model biological systems on a chip.  These chips are devices with specific cell types in chambers that are connected through microfluidic channels to better model the tissues and organs in the human body and how they interact with one another.

Chips could be developed that are made of up cells of the various organs that make up our gastrointestinal tract.  These organoids could then be populated by bacteria that make up the microbiota. Food could be passed through the chip and scientists could watch bacteria break down food that is passing through it and see how the microbiota adapts to changes in diet. Various conditions could be tested such as what bacterial strains are best at digesting complex carbohydrates? The authors state that many combinations of bacterial strains should be tested to find what bacteria conduct these tasks most efficiently. To do this in mice would require thousands of animals and this may be too restrictive to conduct such experiments. This however could be done using chips with stem cell derived tissues that make up our GI tract and connected through microfluidic channels to stem cell derived liver and pancreas cells that are important for nutrition and digestion.

Significant biological and engineering challenges still exist before this is a reality, including the ability for specific strains of bacteria to thrive in such an environment.  However, if some challenges can be overcome, the authors propose that the complexity of nutrition and digestion could be better dissected using systems of stem cell derived tissues in the dish.  This work would complement existing research using model organisms and epidemiological and other human studies to better address the questions that we ask every day about what food we should eat and the effects this has on the human body. 

Diet plays a more important role than genetics in shaping the microbiome in mice

Today is December 31st which means it’s time to make our New Years Resolutions! Luckily for all of us, a new paper by Peter Turnbaugh’s laboratory gives us good reason to make improving our diet an important goal for the New Year. Dr. Turnbaugh and colleagues at Harvard University and University of California, San Francisco have shown that diet plays the dominant role over genetics in shaping the gut microbiome in mammals. 

Published in Cell Host and Microbe, the team of scientists used several strains of mice to investigate whether diet or the genetics of the mice played a more important role in what bacteria colonized the gut.  They exposed the mice to a low-fat, plant-based (LFPP) diet and a high-fat, high-sugar (HFHS) diet. When mice were given the HFHS, an increase in Firmicutes bacteria and a decrease in Bacteroidetes bacteria was seen, regardless as to what their genetic background was.  When the LFPP diet was given, the shift went in the other direction.  Further investigation needs to be done to better understand whether diet plays a direct role in shaping the bacterial communities in the gut or if it is due to an indirect role that the food has on the entire body of the host.

Another important takeaway from the study was that most changes to the microbiome are reversible. This means that once you shift to a new diet, the microbiome changes with the new diet and the new microbial communities are established within 3 days of exposure to the new diet.  However, the microbiome does remember past dietary patterns.  They leave an imprint on the microbial communities in the gut and some bacterial species are dependent on prior consumption.  

Dr. Turnbaugh suggests that in the future it may be possible to design diets that shape the microbiome in ways that are therapeutically beneficial.  He also states that due to this finding that diet plays a more important role than genetics on establishing gut bacteria, diets won’t need to be tailored to every individual person and specific diets may be useful for most people. 

So while you make your New Years Resolution to eat better and have a healthier diet, know that you are not only impacting your nutritional intake but you are also shaping your microbiome.

We wish all of our readers a happy and healthy New Year. This has been a particularly exciting first year for us and we look forward to another great year ahead.  

Changes in the microbiome may affect how we age

Betty White has aged so well because of her microbiome.  Photo by David Shankbone, 2010

Many people have researched the microbiome shift between infancy and adolescence, but very few have researched the changes in the microbiome that occur in the elderly.  A new study out of Canada, published in the Journal Microbiome, did just that.  Their results show that the frailty associated with old-age may be related to the bacteria in our guts.

The study used groups of mice that were either young, middle aged, or old.  They then measured the frailty of these mice which, as one would expect, was tied closely with age.  The researchers then studied the microbiome of these mice, as well as the genes expressed by the bacteria, so as to gain an understanding of what the bacteria are actually doing.

The scientists discovered that, when compared to young and middle aged mice, the old mice were abundant in bacteria that could break down simple sugars, but were underrepresented in bacteria that could break down more complex sugars, as well as lactate.  This is important because increased lactate in the stool has been associated with ulcerative colitis and other inflammatory bowel diseases in older humans.  The old age mice also consisted of less bacteria that could produce vitamins B12 and B7.  Both are important vitamins and the lack of B7 has been linked to colon cancer.  Finally, the old-age mice had bacteria that would rapidly degade creatine.  Creatine is known to build muscle, so constantly breaking it down may cause the decrease in muscle mass observed in the elderly.

Clearly there are changes in the microbiome as we age, and these changes must come with some consequences.  As the authors of this paper suggest, perhaps the microbiome holds to key to the difference between aging like a fine wine and aging like moldy cheese.

Is our virome lowering our intelligence?

We have talked about the virome and its possible substantial impact on human health on this blog before.  Lately, the virome has been getting a lot of press about its potential beneficial aspects, but today we want to discuss a negative one.  A paper was recently published in the Proceedings of the National Academy of Sciences that identified a specific virus in the virome that may be directly affecting the brain, and lowering our aptitude for spatial awareness and attention. 

Researchers were testing the oral microbiome of a cohort of people who were also taking intelligence tests as part of a separate, unrelated, study.  After genome sequencing they noticed the conspicuous existence of a virus, known as Chlorovirus ATCV-1, in about half the study population.  This virus was known to exist in algae, but had never been identified in humans, and there it was, affecting half there population.  Moreover, the virus cut across all demographics in there study, and was not related to age, race, or gender.  When the scientists compared the intelligence tests of those who had the virus versus those that did not, those that had the virus scored slightly less on tests involving spatial awareness.  However, they are quick to note that other tests for intelligence were unaffected.  They reiterate that these scores were related to the existence of the virus and not any specific demographic.

The scientists tried to recreate these results in mice.  They infected a group of mice with the virus and compared its scores on spatial tests with a control group.  The group that had the virus scored considerably lower on the tests.  When they measured specific genes that were affected in the infected mice they discovered some that related to dopamine regulation, which is known to be critical to memory formation and learning. 

Overall this fascinating study not only identified a new member of our virome, but showed that this virus may be altering our spatial reasoning abilities.  So the next time your significant other yells at you for getting lost, just blame it on your virome!

Obesity, mental illness, and the microbiome

A study published by Biological Psychiatry studied the neurological effects of gut bacteria typically part of the obese microbiome, because obesity, depression, and the microbiome have each been associated with one another.  To do this, 8-week-old male mice were fed either a regular chow diet or a high-fat diet. The microbiomes of these mice were then transplanted into 3-month-old male mice that were on a regular chow diet and antibiotics (the antibiotics were used in place of germ free mice to keep their gut populations low).  16S sequencing eventually showed successful transplantation of the donor microbiome to the recipient mice.

The recipient mice were subjected to anxiety, exploratory, stereotypical behavioral testing, as well as memory testing, all of which are common techniques that test for anxiety and depression in mice. In addition, the mice’s microbiomes and blood were sampled, and the mice’s guts and brains were investigated post-mortem.

Results of the experiment showed that the recipient mice, which were raised conventionally, showed significant disruption of mental behavior after harboring the gut microbiome of obese mice that eat a high-fat diet.  Furthermore, these mice had lower microbiome diversity, higher gut permeability (i.e. leaky guts), and higher levels of overall inflammation and brain inflammation than mice with the normal chow transplants.  It is not understood exactly how gut bacteria affect behavior, but it is further evidence of the importance of the gut-brain axis and the potential value of prebiotic and probiotic therapeutics for mental health.  

Probiotics and diet affect mouse offspring gender and survival

An article published in late September by researchers at the Massachusetts Institute of Technology in the Journal of Probiotics and Health shows the importance of the maternal microbiome in the gender and survival of their offspring. Eight-week-old female mice were fed a control diet, a diet representing human fast food consumption, or a diet in which their drinking water was supplemented by the probiotic Lactobacillus reuteri, a bacterium that has been implicated in female oxytocin regulation. Another group of oxytocin-deficient female mice were fed a control diet, or a control diet supplemented by the probiotic. The mice were mated and offspring were observed for three generations.

The researchers concluded that offspring survival increased when mice were given L. reuteri in their diets, and survival decreased significantly with the consumption of a ‘fast food’ diet when compared to the control group. They also concluded that probiotic-treated wild type mothers had an increase in number of female offspring.  However, no increase in female progeny was observed in the probiotic treated mice that were oxytocin deficient, suggesting that probiotic exposure affects levels of oxytocin in females, and this leads to the increase in female offspring.

This research is significant in that it links probiotic intake of mothers to survival of offspring and sex of offspring. It also shows a possible relationship between the microbiome and the hormone oxytocin, which is linked to reproductive and social behavior in female mammals.